Targeting MYC-enhanced glycolysis for the treatment of small cell lung cancer

• Main Authors: Kasey R. Cargill, C. Allison Stewart, Elizabeth M. Park, Kavya Ramkumar, Carl M. Gay, Robert J. Cardnell, Qi Wang, Lixia Diao, Li Shen, You-Hong Fan, Wai Kin Chan, Philip L. Lorenzi, Trudy G. Oliver, Jing Wang, Lauren A. Byers
• Format: Article
• Language: English
• Published: BMC 2021-09-01
• Series: Cancer & Metabolism
• Subjects: MYC; Glycolysis; Metabolism; Small cell lung cancer; PFK158
• Online Access: https://doi.org/10.1186/s40170-021-00270-9

Abstract Introduction The transcription factor MYC is overexpressed in 30% of small cell lung cancer (SCLC) tumors and is known to modulate the balance between two major pathways of metabolism: glycolysis and mitochondrial respiration. This duality of MYC underscores the importance of further investigation into its role in SCLC metabolism and could lead to insights into metabolic targeting approaches. Methods We investigated differences in metabolic pathways in transcriptional and metabolomics datasets based on cMYC expression in patient and cell line samples. Metabolic pathway utilization was evaluated by flow cytometry and Seahorse extracellular flux methodology. Glycolysis inhibition was evaluated in vitro and in vivo using PFK158, a small molecular inhibitor of PFKFB3. Results MYC-overexpressing SCLC patient samples and cell lines exhibited increased glycolysis gene expression directly mediated by MYC. Further, MYC-overexpressing cell lines displayed enhanced glycolysis consistent with the Warburg effect, while cell lines with low MYC expression appeared more reliant on oxidative metabolism. Inhibition of glycolysis with PFK158 preferentially attenuated glucose uptake, ATP production, and lactate in MYC-overexpressing cell lines. Treatment with PFK158 in xenografts delayed tumor growth and decreased glycolysis gene expression. Conclusions Our study highlights an in-depth characterization of SCLC metabolic programming and presents glycolysis as a targetable mechanism downstream of MYC that could offer therapeutic benefit in a subset of SCLC patients.